Tetrahydrothiopyrano(3,2-b)-indole derivatives

ABSTRACT

Tetrahydrothiopyrano[3,2-b]indole derivatives represented by the formula I: ##STR1## wherein R 1  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, phenyl-C 1-4  alkyl, C 2-5  alkanoyl, or ##STR2##  wherein Y is C 1-4  alkylene or C 1-4  oxoalkylene and R 5  and R 6  each is hydrogen or C 1-4  alkyl; 
     R 2  is hydrogen, C 1-4  alkyl or C 3-6  cycloalkyl; 
     R 3  is hydrogen, C 1-4  alkyl or ##STR3##  wherein Y, R 5  and R 6  each is as defined above; or ##STR4##  is pyrrolidino, piperdinyl, piperazinyl, 4-C 1-4  alkylpiperazinyl or morpholino; 
     R 4  is hydrogen or C 1-4  alkyl; and 
     n is 0 or an integer of 1 or 2 
     and the pharmaceutically acceptable salts being useful as analgesic and anti-inflammatory agents as well as psychoanaleptic and nootropic drug.

This application is a Continuation of application Ser. No. 409,107 filedAug. 18, 1982, now abandoned, which is a Continuation-In-Part ofapplication Ser. No. 227,203 filed Jan. 22, 1981, now abandoned.

The present invention relates to noveltetradhydrothiopyrano[3,2-b]indole derivatives and pharmaceuticallyacceptable salts thereof and to a process for the preparation thereof.

The tetrahydrothiopyrano[3,2-b]indole derivatives and theirpharmaceutically acceptable salts are useful medicaments exhibitinganalgesic and anti-inflammatory activities. Additionally, they areuseful as psychoanaleptic and nootropic drugs.

Tetradhydrothiopyrano[2,3-b]indole derivatives having a sulfur atom atthe reversal position in the thiopyrane ring are already known to haveanalgesic and anti-inflammatory activities (U.S. Pat. No. 4,256,640).Psychotropic activity for such compounds, however, has not been known.Additionally, the compounds decrease spontaneous locomotion and havehallucinogenic activity. There is little hope of the clinicalapplication of the compounds because of these adverse side effects. Onthe contrary, the compounds of this invention moderately increasespontaneous locomotion and have no hallucinogenic activity. Furthermore,they have psychoanaleptic or nootropic activities. Accordingly, thepresent invention provides very valuable novel compounds.

Specifically, this invention provides a compound of the formula [I]:##STR5## wherein R¹ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,phenyl-C₁₋₄ alkyl, C₂₋₅ alkanoyl, or ##STR6## wherein Y is C₁₋₄ alkyleneor C₁₋₄ oxoalkylene and R⁵ and R⁶ each is hydrogen or C₁₋₄ alkyl;

R² is hydrogen, C₁₋₄ alkyl or C₃₋₆ cycloalkyl;

R³ is hydrogen, C₁₋₄ alkyl or ##STR7## wherein Y, R⁵ and R⁶ each is asdefined above; or ##STR8## is pyrrolidino, piperidinyl, piperazinyl,4-C₁₋₄ alkylpiperazinyl or morpholino;

R⁴ is hydrogen or C₁₋₄ alkyl; and

n is 0 or an integer of 1 or 2.

The following definitions are given for various terms used throughoutthis specification.

The term "C₁₋₄ alkyl" refers to straight and branched aliphatic radicalshaving from one to four carbon atoms including, e.g. methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl and the like.

The term "C₂₋₄ alkenyl" refers to a group having one or more doublebonds in the above straight or branched alkyl chain, e.g. vinyl, allyl,butenyl, isobutenyl and the like.

The term "C₂₋₄ alkynyl" refers to a group having one or more triplebonds in the above straight or branched alkyl chain including e.g.ethynyl, 1-propynyl, 2-propynyl, 2-butynyl and the like.

The term "C₃₋₆ cycloalkyl" includes cyclopropyl, cyclobutyl, cyclohexyland the like. Additionally, C₂₋₅ alkanoyl includes e.g. acetyl,propionyl, butyryl, isobutyryl, valeryl and the like.

The group ##STR9## includes aminoalkyl, C₁₋₄ alkylaminoalkyl,N,N-di-C₁₋₄ alkylaminoalkyl and their oxo-substituted equivalents (e.g.aminomethyl, methylaminomethyl, isopropylaminomethyl, methylaminoethyl,ethylaminopropyl, N,N-dimethylaminomethyl, N,N-diethylaminoethyl,N,N-dimethylaminopropyl, carbamoyl, N-methylaminoacetyl and3-(N,N-dimethylamino)-2-oxo-propyl).

In the above definitions, the preferable R⁴ is hydrogen and methyl; themost preferred is hydrogen. The preferably n is 0 and 1 and the mostpreferred is 0. The preferred R¹ is hydrogen and C₁₋₄ alkyl; methyl isthe most preferred R¹. The prefered R² is hydrogen and C₁₋₄ alkyl,especially methyl and the preferred R³ is C₁₋₄ alkyl, especially methyland N,N-di-C₁₋₄ alkylaminoethyl, especially 2-N,N-diethylaminoethyl. Thegroup ##STR10## is preferably N-C₁₋₄ alkylaminoethyl, N,N-di-(C₁₋₄alkyl)aminomethyl and N-C₁₋₄ alkyl-N-[2-N',N'-di-(C₁₋₄alkyl)aminoethyl]aminomethyl, especially methylaminomethyl,N,N-dimethylaminomethyl and N-methyl-N-(2-N',N'-diethylaminoethyl)aminomethyl, respectively; the most preferred groupis methylaminomethyl.

The representative compounds of formula I are as follows:

Compounds of formula I wherein n is 0, R⁴ is hydrogen,

1. R¹ and R² each is hydrogen and R³ is methyl,

2. R¹ is hydogen and R² and R³ each is methyl,

3. R¹ is hydrogen, R² is methyl and R³ is 2-(N,N-diethyl)aminoethyl,

4. R¹ is hydrogen and R² and R³ taken together form piperadinyl,

5. R¹ is methyl, R² is hydrogen and R³ is methyl,

6. R¹ is methyl, R² is hydrogen and R³ is ethyl,

7. R¹ is methyl, R² is hydrogen and R³ is isopropyl,

8. R¹ is methyl, R² is cyclohexyl and R³ is hydrogen,

9. R¹, R² and R³ each is methyl,

10. R¹ is methyl and R² and R³ each is ethyl,

11. R¹ and R² each is methyl and R³ is propyl,

12. R¹ and R² each is methyl and R³ is 2-N,N-dimethylaminoethyl,

13. R¹ and R² each is methyl and R³ is N,N-diethylcarbamoylmethyl,

14. R¹ and R² each is methyl and R³ is methylaminomethyl,

15. R¹ is methyl and R² and R³ taken together form pyrrolidino,

16. R¹ is methyl and R² and R³ taken together form N-methylpiperazinyl,

17. R¹ is methyl and R² and R³ taken together form morpholino,

18. R¹ is ethyl, R² is hydrogen and R³ is methyl,

19. R¹ is ethyl, R² is hydrogen and R³ is ethyl,

20. R¹ is ethyl, R² is hydrogen and R³ is isopropyl,

21. R¹ is ethyl and R² and R³ each is methyl,

22. R¹ is ethyl, R² is hydrogen and R³ is 2-N,N-dimethylaminoethyl,

23. R¹ is ethyl, R² and R³ taken together form piperidinyl,

24. R¹ is propyl, R² is hydrogen and R³ is methyl,

25. R¹ is propyl and R² and R³ each is methyl,

26. R¹ is propyl, R² is methyl and R³ is2-N,N-dimethylaminotrimethylene,

27. R¹ is propyl and R² and R³ taken together form piperazinyl,

28. R¹ is isopropyl, R² is hydrogen and R³ is methyl,

29. R¹ is isopropyl and R² and R³ each is methyl,

30. R¹ butyl, R² is hydrogen and R³ is methyl,

31. R¹ is butyl, R² is methyl and R³ is 2-N,N-diethylaminoethyl,

32. R¹ is vinyl, R² is hydrogen and R³ is methyl,

33. R¹ is allyl, R² is hydrogen and R³ is methyl,

34. R¹ is allyl and R² and R³ each is methyl,

35. R¹ is 2-propynyl, R² is hydrogen and R³ is methyl,

36. R¹ is 2-propynyl and R² and R³ each is methyl,

37. R¹ is 2-propynyl and R² and R³ taken together formN-methylpiperazinyl,

38. R¹ is benzyl, R² is hydrogen and R³ is methyl,

39. R¹ is benzyl and R² and R³ each is methyl,

40. R¹ is acetyl, R² is hydrogen and R³ is methyl,

41. R¹ is acetyl and R² and R³ each is methyl,

42. R¹ is propionyl, R² is hydrogen and R³ is methyl,

43. R¹ is propionyl and R² and R³ each is methyl,

44. R¹ is N,N-diethylaminomethyl, R² is hydrogen and R³ is methyl,

45. R¹ is 2-N-methylaminoethyl, R² is hydrogen and R³ is methyl,

46. R¹ is 2-N,N-diethylaminoethyl, R² is hydrogen and R³ is methyl,

47. R¹ is N-methylcarbamoylmethyl, R² is hydrogen and R³ is methyl,

48. R¹ is N,N-diethylcarbamoylmethyl, R² is hydrogen and R³ is methyland

49. R¹ is N,N-diethylcarbamoylmethyl and R² and R³ each is methyl;Compounds of formula I wherein n is 0, R⁴ is methyl,

50. R¹ and R² each is hydrogen and R³ is methyl,

51. R¹ is hydrogen and R² and R³ each is methyl,

52. R¹ is methyl, R² is hydrogen and R³ is methyl,

53. R¹ is methyl, R² is hydrogen and R³ is ethyl,

54. R¹ is methyl, R² is hydrogen and R³ is isopropyl,

55. R¹ and R² each is methyl and R³ is 2-N,N-dimethylaminoethyl,

56. R¹ is ethyl, R² is hydrogen and R³ is methyl,

57. R¹ is ethyl and R² and R³ each is methyl,

58. R¹ is ethyl and R² and R³ taken together form pyrrolidino,

59. R¹ is allyl, R² is hydrogen and R³ is methyl; Compounds of formula Iwherein n is 0, R⁴ is ethyl,

60. R¹ is methyl, R² is hydrogen and R³ is methyl,

61. R¹ is methyl and R² and R³ each is ethyl; Compounds of formula Iwherein n is 0, R⁴ is propyl,

62. R¹, R² and R³ each is methyl; Compounds of formula I wherein n is 1,R⁴ is hydrogen,

63. R¹ is methyl, R² is hydrogen and R³ is methyl,

64. R¹, R² and R³ each is methyl,

65. R¹ is ethyl, R² is hydrogen and R³ is methyl, and

66. R¹, R², and R³ each is ethyl; Compounds of formula I wherein n is 1,R⁴ is methyl;

67. R¹ is methyl, R² is hydrogen and R³ is methyl, and

68. R¹, R² and R³ each is methyl, Compounds of formula I wherein n is 2,R⁴ is hydrogen,

69. R¹ is methyl, R² is hydrogen and R³ is methyl,

70. R¹ is ethyl, R² is hydrogen and R³ is methyl, and

71. R¹ is ethyl and R² and R³ each is methyl and their salts.

The compound of this invention (hereinafter referred to as Compound [I])includes 4-(substituted orunsubstituted-amino)methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]idolesoptionally having a substituent at the 4 and/or 5 position, and thesulfur atom at the 1 position may be oxide or dioxide. Further, thisinvention includes the pharmaceutically acceptable salts of Compound[I], for example, hydrochloride, hydrobromide, hydroiodide, sulfate,phosphate, methanesulfonate, acetate, citrate, oxalate, fumarate,malate, succinate, maleate, phthalate, cinnamate, benzoate, ascorbateand the like.

Compound [I] is novel. A compound having the2,3,4,5-tetrahydrothiopyrano[3,2-b]indole nucleus with any recognizedpharmaceutical activity has not yet been known. Naturally, it is notknown that Compound [I] has analgesic, anti-inflammatory and/orpsychoanaleptic and nootropic activities.

Compound [I] can be prepared by various methods, one of which isillustrated as follows: ##STR11## (wherein R¹,R², R³, R⁴ and n each isas defined above) (1) Starting Compound [IV]

Thiol derivative [IV] is prepared by Harris's method: TetrahedronLetters, 1969, 4465. Namely, indole or 1-substituted indole is treatedwith thiourea in the presence of iodine-potassium iodide and theresulting isothiuronium salt is hydrolyzed by alkali. Besides,3-indolylthiol has been prepared by Harris and 1-methyl-3-indolylthiolby Marches: Chim. Ind. (Milan.), 51, 41 (1969).

(2) Process for preparing Compound [III] (Step (a))

Compound [III] is prepared by reacting Compound [IV] with4-halogeno-2-butyn-1-ol in the presence of a dehydrohalogenating agent.The reaction is carried out in an inert organic solvent at roomtemperature or under heating.

(3) Process for preparing Compound II (Step (b))

Compound [II] can be prepared by cyclizing

Compound [III] under heating. The reaction is carried out in an inertorganic solvent (e.g. benzene, toluene, xylene, dimethylformamide,dimethylsulfoxide, alcohols, pyridine, dimethylaniline and the like).

(4) Process for preparing Compound [I]

Various routes can be taken to prepare Compound [I] from Compound [II]depending on the objective Compound [I]. A few typical methods are shownas follows:

a. Formation of aminomethyl or substituted aminomethyl group

The formyl group at the 4 position of Compound [II] can be convertedinto aminomethyl, for example, by reacting Compound [II] with ammonia ora primary or secondary amine under reductive conditions or followed byreduction, if necessary. The reaction of Compound [II] and an amine iscarried out in an inert organic solvent, e.g. benzene, or alcohols, atroom temperature or under heating. The resultant Schiff base is treatedwith a reducing agent such as metal hydride, sodium-alcohol, formic acidand the like. Formic acid is preferably used when a secondary amine isreacted . The reduction can proceed without isolation of the resultantSchiff base. Further, the reaction of Compound [II] can be effected withan amine under reaction conditions, namely in the presence of a suitablereducing agent to give the desired Compound [I].

b. Introduction of R⁴

Alkylation of Compound [I] in which R⁴ is hydrogen is effected in ausual manner and gives the objective Compound [I] in which R⁴ is nothydrogen. There is exemplified an alkylation by using an alkali metalcompound (e.g. sodium hydride, potassium hydroxide) and alkyl, halide(e.g. methyl iodide) in an inert organic solvent (e.g.dimethylformamide, dioxane, dimethylsulfoxide).

c. Introduction and substitution of R¹

R¹ can be introduced into Compound [I] in which R¹ is hydrogen in thesame manner as in the above b. Further, R¹ can be replaced by anotherdesired R¹ by removing the former R¹ in a conventional manner followedby introducing another substituent R¹.

d. S-Oxidation

Oxidation of the sulfur atom at the 1 position (formation of sulfide andsulfoxide) can be carried out by a conventional method. The reaction iscarried out with a conventional pereacid (e.g. perchloric acid, periodicacid, perbenzoic acid, m-chloroperbenzoic acid) in an inert organicsolvent at room temperature or under heating.

e. Other modification

Additionally to the above modification, a variety of modifications andsubstitutions may be effected by usual methods. Further, the product maybe converted into the desired salt. The salt formation can be carriedout in a conventional manner.

Besides, a reactive substituent of Compounds [I] and [II] may beprotected at any step in the above steps a to e, if necessary, and theprotecting group may be removed at a suitable step if required.

For example, nitrogen at the position 5 is protected with a suitableprotecting group, for example, acyl (e.g. acetyl, trifluoroacetyl),alkoxyalkyl (e.g. methoxymethyl), benzyl and the like before analkylamino or dialkylamino group is introduced into the formyl group atthe position 4. The protecting group is removed in a usual manner, forexample, with an acid when the protecting group is acyl or alkoxyalkyland with sodium metal in liquid ammonia when the protecting group isbenzyl after accomplishment of modification of the position 4.

On the contrary, the aminomethyl group at the position 4 may beprotected during the modification of the nitrogen at the position 5. Acommon amino-protecting group, for example, acyl (e.g. acetyl,trifluoroacetyl), alkoxyalkyl (e.g. methoxymethyl) and t-butoxycarbonylgroup may be used to protect the amino or imino group at the aminomethylor N-mono substituted aminomethyl at the position 4. The protectinggroup is removed by the usual method, for example, with an acid (e.g.hydrochloric acid, sulfuric acid); trifluoroacetic acid is preferablyused when the protecting group is a t-butoxycarbonyl group aftercompletion of the modification of the nitrogen atom at position 5. Thesame protecting procedure is effected when Compound [I] is subjected tooxidation.

Some typical compounds of this invention were examined for physiologicalactivities. The results are shown as follows:

1. Test Method

(1) Anti-inflammatory activity (Carrageenin edema method)

A 0.9% saline solution (0.05 ml) containing 1.0% carrageenin is used asphlogistic agent. After 30 minutes JCl-Wistar female rats (180-200 g,body weight) are orally administered a test compound, the phlogisticagent is injected subcutaneously into the plantar of the feet of therats. The volume of swelling is measured 3 hours later and theanti-edema activity is determined by calculating a ratio (%) of theedematous volume of medicated foot to that of non-medicated foot.

(2) Analgesic activity (Acetic acid writhing method)

DS male mice (20-23 g, body weight) are treated with an intraperitonealinjection of 0.1 ml/10 g of 0.6% acetic acid 30 minutes after oraladministration of a test compound. The number of writhing times for 10minutes is counted and ED₅₀ is calculated.

(3) Acute toxicity

DS mice (20-23 g, male) are orally administered a suspension of testcompound with gum arabic. The mortality at the 72nd hour is determinedand the LD₅₀ is calculated.

(4) Antidepressant activity

(4)-a Anti-tetrabenazine ptosis test

Tetrabenazine (TBZ, 50 mg/kg s.c.) was administered to 5 mice for eachgroup 1 hour after oral treatment with test compounds. Degree of theptosis was measured 1 hour after TBZ administration according to themethod of Janssen et al. (Arzneim.-Forsch./Drug Res. 15 104 (1965)).(4=complete, 3=3/4, 2=1/2, 1=4/1 closure of the eyelid, 0=normal).

(4)-b Anti-electroshock test with reserpine

Test compounds were administered (p.o.) 0.5 hour before reserpine (2.5mg/kg s.c.) and the mice were subjected to minimal electroshock seizuresaccording to the method of Swinyard et al. (J. Pharmacol. Exp. Ther. 106319-330 (1952)). Seizures were induced by shocking mice (10 per dose)via a pair of corneal electrodes with current intensity of 12 mA and aduration of 0.2 sec 4 hours after administration of reserpine.

(5) Anti-cholinergic activity (Anti-oxotremorine hypothermia test)

Before each experiment the rectal temperature of the mice was recordedwith a probe thermometer at a constant depth. The mice were divided intogroups of 8 in such a way that the mean rectal temperature was the samein each group. Test compounds were administered orally 30 minutes befores.c. administration of oxotremorine (0.5 mg/kg).

(6) Spontaneous locomotor increasing activity

For each group 3 mice were used. Spontaneous locomotor activity wasrecorded for 15 minutes by a Varimex activity meter from 15 minutesafter oral administration of a test compound. The ED₅₀ value was definedas the dose that resulted in 50% increase of the spontaneous locomotoractivity compared to the control value.

(7) Spontaneous locomotor decreasing activity

For each group 5 mice were used. Spontaneous locomotor activity wasrecorded for 10 minutes by a Varimex activity meter from 60 minutesafter oral administration of a test compound. The ED₅₀ value was definedas the dose that resulted in a 50% decrease of the spontaneous locomotoractivity compared to the control.

(8) Hallucinogenic activity

Each of the five mice in each group was confined n a box for 15 minutesto let it adapt to its surroundings. The mouse was kept on a black discof 74 cm in diameter for 2 minutes from 5 and 15 minutes afteradministration of a test compound. The number of bizarre behaviours(walking backwards, pivoting and the like) was counted.

2. Results

The results are shown in Tables 1-4 and FIGS. 1 and 2, wherein FIG. 1shows the hallucinogenic activity of a compound of the presentinvention, and FIG. 2 shows the hallucinogenic activity of a referencecompound.

                                      TABLE 1                                     __________________________________________________________________________                                  Test                                                                              Test                                                                              Test                                    Test                          (1) (2) (3)                                     Comp.                                                                             Structure.sup.1      Addition                                                                           ED.sub.30                                                                         ED.sub.50                                                                         LD.sub.50                               No. R.sup.1  R.sup.2                                                                         R.sup.3 n salt mg/kg                                                                             mg/kg                                                                             mg/kg                                   __________________________________________________________________________    1   Me.sup.2 Me                                                                              H       0 HCl  9.4 6.4 400                                     2   Et.sup.3 Me                                                                              H       0 Oxalate                                                                            9.4 13.3                                                                              800                                     3   Me       Me                                                                              Me      0 "    28.3                                                                              17.8                                                                              400                                     4   Me       Me                                                                              H       1 --   --  49.0                                                                              >1000.sup.5                             5   CH.sub.2CHCH.sub.2                                                                     Me                                                                              H       0 Oxalate                                                                            17.5                                                                              11.3                                                                              700                                     6   Me       Me                                                                               ##STR12##                                                                            0 "    13.4                                                                              25.3                                                                              700                                     Ref..sup.4               HCl  --  4.2 330                                     Aminopyrine                   24  58  800                                     __________________________________________________________________________     Notes:                                                                        ##STR13##                                                                     .sup.2 Me = methyl                                                            .sup.3 Et = ethyl                                                             .sup.4 Ref. = 4methylaminomethyl-2,3,4,9-tetrahydro-thiopyrano                [3,2b]indole HCl salt (a compound claimed in U.S. Pat. No. 4,256,640)         .sup.5 ">1000" means that LD.sub.50 value is more than 1000 mg/kg and the     precise amount was not determined.                                       

                  TABLE 2                                                         ______________________________________                                        Anti-depressant and anti-cholinergic activities                               Test Item       Comp. 1   Ref.    Imipramine                                  ______________________________________                                        Anit-depressant Act.                                                          (4)-a Anti-tetrabenazine Ptosis                                                               24.4      >50     6.0                                         M ED.sub.50                                                                   (4)-b Anti-electroshock with                                                                   4.3      8.4     101.6                                       Reserpine                                                                     M ED.sub.50                                                                   Anti-cholinergic Act.                                                         (5) Anti-oxotremorine                                                                         >50       >50     4.5                                         hypothermia                                                                   M ED.sub.50                                                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Increasing effects on spontaneous locomotion in                               mice                                                                                                            ED.sub.50 mg/kg                                        Dose    No. of  % of   (95% confidence                             Compound   mg/kg   groups  increase                                                                             limits)                                     ______________________________________                                        Comp. 1    2.5     5       (9.1)                                                         5       "       54.3   5.6                                                    10      "       91.4   (4.89-6.27)                                            20      "       123.0                                              Methamphetamine                                                                          0.25    5       (3.8)                                                         0.5     "       45.4   0.6                                                    1       "       62.5   (0.48-0.74)                                            2       "       137.8                                              ______________________________________                                         ( ):inhibition                                                           

                  TABLE 4                                                         ______________________________________                                        Decreasing effects on spontaneous locomotion in                               mice                                                                                                           ED.sub.50 mg/kg                                       Dose    No. of  % of    (95% confidence                              Compound mg/kg   groups  decrease                                                                              limits)                                      ______________________________________                                        Ref.     25      5        7.4    43.0                                                  50      "       75.3    (36.6-49.7)                                           100     "       97.2                                                 Imipramine                                                                             25      5       19.1    56.0                                                  50      "       56.0                                                          100     "       62.9    (47.2-78.4)                                  ______________________________________                                    

As shown in Table 1, the above tested compounds have analgesic andanti-inflammatory activities. The analgesic activity is much strongerthan a commercially available analgesic, aminopyrine.

Table 2 shows that Compound 1 has strong anti-depressant activitycompared with an anti-depressant on the market, imipramine. Favourably,the compound of this invention has no anti-cholinergic acitivity.

Furthermore, Compound 1 moderately increases spontaneous locomotion inmice as shown in Table 3 although the reference compound in the priorart, U.S. Pat. No. 4,256,640 decreases the activity as shown in Table 4.Compound 1 does not have so strong increasing activity asmethamphethamine, while continuous administration of Compound 1maintains mild activity for more than 24 hours. The activity ofmethamphethamine continues only 2 to 3 hours even though by successiveadministration. Therefore, Compound 1 can be used as psychoanaleptic ornootropic drug having a mild and long lasting effect.

Favourably, Compound 1 has no hallucinogenic activity although thereference compound does as shown in FIGS. 1 and 2. Thus, Compound 1 canbe used repeatedly for a long time as analgesic and anti-inflammatoryagent as well as psychoanaleptic or nootropic drug.

The other compounds of this invention have nearly the samepharmacological acitivities. Accordingly, Compound [I] of this inventioncan be used as an analgesic and anti-inflammatory agent and apsychoanaleptic or nootropic drug.

Practically, Compound [I] and its pharmaceutically acceptable salts canbe applied to treatment of various ailments, pains and mental diseasesof humans and other animals.

The compounds of this invention can be administered along or incombination with pharmaceutically acceptable carriers and other drugs,if necessary, orally, percutaneously or by injection. Preferably, thecompounds are used in combination with one or more carriers suited tothe particular route of administration. Examples of solid carriers forinternal or external use are lactose, sucrose, starch, dextrin, sodiumbicarbonate, licorice powder, talc, kaoline, bentonite, calciumcarbonate, paraffin and the like, and as gel or liquid carrier,gelatine, water, ethanol, isopropanol, chloroform, glycerol, and thelike are exemplified.

Practical examples of suitable forms of pharmaceutical preparation ofCompound [I] are tablets, capsules, pills, ointments, granules, powders,suppositories, aerosols and injectable solutions.

The invention also provides a therapeutic formulation which comprises 1mg to 100 mg of one or more Compound [I] with or without apharmaceutically acceptable carrier. Compound [I] is generallyadministered to human adults in an amount of about 5 to about 100 mg ata time, thought the amount may largely be varied depending onconditions, e.g. case history, age and sex of the patient,administration route and the like. The compound can be administered tohumans either in a single or divided doses. The compound may also beadministered at once for acute diseases. Thus, the invention includes amethod for giving analgesic, psychoanaleptic and nootropic effects to ananimal, which method comprises administering an effective amount of aCompound [I] to the animal.

The invention will now be further illustrated and described by way ofthe following examples.

EXAMPLE 1

A-(1) 1-Ethyl-3-indolylthiol

A solution of 1-ethylindole (25 g) and thiourea (15.7 g) in methanol(400 ml) is mixed with an aqueous solution (250 ml) of potassium iodide(34.4 g) and iodine (26.3 g) and allowed to stand at room temperaturefor 2 hours. The mixture is stirred for 1 hour and condensed to giveS-(1-ethyl-2-indolyl)isothiuronium iodide:mp. 225.5°-228° C. (decomp.).To the product is added 5% aqueous sodium hydroxide solution (200 ml).The mixture is heated at 90° C. for 10 minutes in argon atmosphere,washed with ether, acidified with a dilute hydrochloric acid andimmediately extracted with ether. The extract is washed with water,dried and evaporated to give the title compound as a yellow oil: Yield58.4%.

IR:ν_(max) ^(CHCl) 3 2540 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 1.35t(J=7, 3H) 2.82d(J=2, 1H, D₂ O disappears)4.02q(J=7, 2H).

A-(2) The same procedure as noted above gives 1-benzyl-3-indolylthiol.

Mp. 78°-80° C.

IR:ν_(max) ^(CHCl) 3 2540 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 2.90d(J=2, 1H, D₂ O disappears) 5.25s(2H).

B-(1) 4-Formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

After successive addition of 1-methyl-3-indolylthiol (15.5 g),4-chloro-2-butyn-1-ol (8.72 g) and potassium carbonate (12.1 g) toacetone (300 ml), the mixture is stirred at room temperature in nitrogenatmosphere for 16 hours. The precipitate is filtered off and thefiltrate is condensed at under 40° C. Diethylamine (5 ml) is added tothe residue. The mixture is allowed to stand for 1 hour at roomtemperature and then water is added thereto, which is extracted withchloroform. The extract is dried and evaporated to dryness. The residueis applied to silica gel chromatography eluted with benzene/petroleumether (4:1) and then benzene-benzene/ether (20:1). The latter fractionsgive 1-methyl-3-(4-hydroxy-2-butynylthio)indole (17.7 g) as yelloworange oil:Yield 78.4%.

IR:ν_(max) ^(CHCl) 3 3600, 2210 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 1.57brs(1H) 3.47t(J=2, 2H) 3.68s(3H) 4.18brt (2H).

δ_(d).sbsb.5_(-py) 3.50s(3H) 3.63t(J=2, 2H) 4.51t(J=2, 2H).

To dry toluene (200 ml) are added the above product (17.5 g) and drypyridine (17.5 ml) and the mixture is refluxed for 15 hours in nitrogenatmosphere and evaporated to dryness. The residue is applied to columnchromatography on silica gel eluted with benzene/petroleum ether (8:1)to give the title compound (13.3 g):mp. 100°-101° C.:Yield 76.0%.Recrystallization from benzene/petroleum benzine gives crystals meltingat 100.5°-102° C.

IR:ν_(max) ^(CHCl) 3 1730 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 3.50s(3H) 3.76m(1H) 9.67d(J=2, 1H).

B-(2) The following compounds are obtained in the same procedure asdescribed above.

4-Formyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole: a paleyellow oil.

IR:ν_(max) ^(CHCl) 3 1720 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 1.29t(J=7, 3H) 3.79m(1H) 4.07q(J=7, 2H) 9.96d(J=2,1H).

4-Formyl-5-benzyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole: mp. 88°-89°C.

IR:ν_(max) ^(CHCl) 3 1725 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 3.62m(1H) 5.62s(2H) 9.47d(J=2, 1H).

EXAMPLE 2

(1)4-Methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

To a solution of4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.2 g) inbenzene (12 ml) is added 10% solution (3.2 g) of methylamine in benzene.The mixture is stirred at room temperature for 2.5 hours and thenevaporated to give4-methyliminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indoleas an oil.

IR:ν_(max) ^(CHCl) 3 1675 cm⁻¹.

NMR:δ_(CDCl).sbsb.3 3.25brs(3H) 3.60s(3H).

The above product is dissolved in methanol (15 ml) and sodiumborohydride (138 mg) is added dropwise thereto with stirring undercooling. The mixture is allowed to stand at room temperature for 2 hoursand evaporated to dryness. The residue is dissolved in chloroform,washed with water, dried and evaporated to give the title compound (1.16g): Yield 90.8%. Recrystallization from benzene/petroleum benzine givescrystals melting at 125°-128° C.

NMR:δ_(CDCl).sbsb.3 2.40s(3H) 3.63s(3H).

Anal. Calcd. for C₁₄ H₁₈ N₂ S:C, 68.25; H, 7.36; N, 11.37. Found: C,68.56; H, 7.18; H, 11.54.

The above product is dissolved in acetone, and ether/hydrochloric acidis gradually added thereto. The precipitated crystals are collected byfiltration to give the hydrochloride: mp. 258°-250° C. (decomp.)

Anal. Calcd. for C₁₄ H₁₉ N₂ SCl: C, 59.45; H, 6.77; N, 9.90. Found: C,59.35; H, 6.87; N, 9.67.

(2) The same procedure as described above gives compound No. 2-2-2-9 inTable 5.

EXAMPLE 3

(1)4-Dimethylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

To 50% aqueous solution (610 mg) of dimethylamine are added 99% formicacid (575 mg) and benzene successively. The mixture is evaporated inorder to remove the water by azeotropic distillation and then thebenzene. A solution of4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.2 g) inbenzene (15 ml) is added to the above residue dropwise over 10 minutesunder heating. The mixture is refluxed for 5 hours, then made alkalinewith sodium hydroxide under ice-cooling and extracted with ether. Theextract is washed with a saline solution, dried and evaporated to givethe title compound (780 mg): Yield 57.7%. Recrystallization frompetroleum benzine gives crystals melting at 81°-83° C.

NMR: δ_(CDCl).sbsb.3 2.25s(6H) 3.55s(3H).

Anal. Calcd. for C₁₅ H₂₀ N₂ S: C, 69.19; H, 7.74; N, 10.76. Found: C,69.31; H, 7.73; N, 10.58.

Oxalate: mp. 228°-229.5° C. (decomp.).

(2) The same procedure as described above gives compound Nos. 3-2-3-6 inTable 5.

EXAMPLE 4

(1) 4-Methylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

Liquid ammonia (ca. 100 ml) is trapped in a solution of4-methylaminomethyl-5-benzyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole(1.6 g) in ether (20 ml) under cooling at -70° C. A piece of sodiummetal is added occasionally under refluxing. The refluxing is continuedfor 1.5 hours after the dark green color of the reaction mixturedisappears. The reaction mixture is neutralized with ammonium chloride,the excess ammonia removed, and then the residue extracted withmethylene chloride after addition of water. The extract is washed withwater, dried and evaporated to give the title compound (1.06 g): Yield91.4%. Recrystallization from benzene-petroleum benzine gives crystalsmelting at 100°-101° C.

IR: ν_(max) ^(CHCl) 3 3460, 3300 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 2.40s(3H) 10.13brs(1H).

Anal. Calcd. for C₁₃ H₁₆ N₂ S: C, 67.20; H, 6.94; N, 12.06. Found: C,67.29; H, 6.97; N, 11.70.

Hydrochloride: mp. 208°-217° C. (decomp.).

(2) The same procedure as described above gives the compound No. 4-2 inTable 5.

EXAMPLE 5

(1)4-Dimethylaminomethyl-5-isopropyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indol

A solution of4-dimethylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.00 g)in dry dimethylformamide (25 ml) is mixed with 50% sodium hydride (293mg) under stirring and the mixture is allowed to stand at 40° C. for 1hour. Then, the reaction mixture is mixed with a solution of isopropyliodide (1.63 g) in dimethylformamide (2 ml) and kept at 40° C. for 2hours and further for 20 hours after addition of the reagent. Thereaction mixture is mixed with ether and ice water successively at under5° C. and the ether layer is separated. The aqueous layer is furtherextracted with ether. The combined ether layers are extracted with adilute hydrochloric acid solution. The extract is made alkaline andextracted with methylene chloride. The extract is washed with water,dried and evaporated to give the title compound (910 mg) as an oil:Yield 77.8%.

NMR: δ_(CDCl).sbsb.3 1.52d(J=7) 1.66d(J=7) 2.27s(6H) 4.56m(J=7,1H).

Oxalate: mp. 135°-138° C. (decomp.).

Anal. Calcd. for C₁₉ H₂₆ N₂ O₄ S: C, 60.29; H, 6.92; N, 7.40. Found: C,60.26; H, 6.86; N, 7.22.

(2) The same procedure as described above gives the compound Nos. 5-2and 5-3 in Table 5.

EXAMPLE 6

(1)4-Methylaminomethyl-5-isopropylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

(a) A solution of4-methylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (5.47 g)in dry tetrahydrofuran (50 ml) is mixed with triethylamine (3.58 g) and2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (5.93 g), allowed tostand at room temperature for 4 hours and evaporated to dryness. Theresidue is dissolved in methylene chloride and washed with a dilutesodium hydroxide solution. The solution is washed with water, dried andevaporated to dryness. The residue is applied to column chromatographyon silica gel eluted with benzene/ether (20:1) to give4-(N-methyl-N-t-butoxycarbonylaminomethyl)-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (5.33 g): Yield 68.2%. Recrystallization frombenzene/petroleum benzine gives crystals melting at 151°-153° C.(decomp.).

(b) A solution of the above product (1.6 g) in dry dimethylformamide (15ml) is mixed with 50% sodium hydride (300 mg) and heated at 40° C. for 1hour. A solution of isopropyl iodide (1.64 g) in dimethylformamide (2ml) is added thereto at 5° C. The mixture is kept at 40° C. for 20 hoursand ether and ice water are successively added at under 5° C. The etherlayer is separated and the aqueous layer is extracted with ether. Theextract is combined with the ether layer, washed with a saline solution,dried and evaporated to give4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-isopropyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indoleas an oil.

IR: ν_(max) ^(CHCl) 3 1680 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 1.50s(9H) 1.54d(J=7) 1.71d(J=7) 2.93(3H) 4.67m(J=7,1H).

The product is dissolved in dry methylene chloride (20 ml), mixed withtrifluoroacetic acid (4 ml) at 10° C. under stirring and allowed tostand at room temperature for 2 hours. The solvent is evaporated atunder 30° C. The residue is dissolved in methylene chloride, washed witha sodiumhydrogen carbonate solution and water successively at under 10°C., dried and evaporated to give the title compound (1.21 g) as a redoil: Yield 91.6%.

NMR: δ_(CDCl).sbsb.3 1.53d(J=7) 1.69d(J=7) 2.45s(3H) 4.60m(J=7, 1H).

Oxalate: mp. 183°-187° C. (decomp.).

Anal. Calcd. for C₁₈ H₂₄ N₂ O₄ S: C, 59.32; H, 6.64; N, 7.69. Found: C,59.12; H, 6.59; N, 7.65.

(2) The same procedure as described above gives compound Nos. 6-2-6-6 inTable 5.

EXAMPLE 7

4-N-Methyl-N-(diethylcarbamoylmethyl)aminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

A solution of4-methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole(0.9 g) in tetrahydrofuran (30 ml) and dimethylformamide (5 ml) is mixedwith triethylamine (740 mg) and a solution of N,N-diethylchloroacetamide(657 mg) in tetrahydrofuran (1 ml) is added dropwise thereto under icecooling with stirring. The mixture is allowed to stand for 3 hours atroom temperature and evaporated to dryness. After addition of water, theresidue is extracted with chloroform. The chloroform layer is washedwith water, dried and evaporated to give the title compound (1.26 g) asan oil: Yield 95.4%.

IR: ν_(max) ^(CHCl) 3 1640 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 2.42s(3H) 3.63s(3H) 4.01s(2H).

Oxalate: mp. 164°-167° C. (decomp.).

Anal. Calcd. for C₂₂ H₃₁ N₃ O₅ S: C, 58.78; H, 6.95; N, 9.35. Found: C,58.83; H, 6.80; N, 9.12.

EXAMPLE 8

4-N-Methyl-N-(N,N-diethylaminoethyl)aminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

A solution of4-N-methyl-N-(diethylcarbamoylmethyl)aminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indoleobtained in Example 7 in tetrahydrofuran is mixed with 3 moles lithiumaluminium hydride and refluxed for 2 hours. The reaction mixture ispoured into ice, made alkaline and extracted with chloroform. Theextract is washed with water, dried and evaporated to give the titlecompound as an oil: Yield 91.1%.

NMR: δ_(CDCl).sbsb.3 1.00t(J=7, 6H) 2.30s(3H) 3.60s(3H).

Dioxalate: mp. 180.5°-184° C. (decomp.).

Anal. Calcd. for C₂₄ H₃₅ N₃ O₈ S: C, 54.84; H, 6.71; N, 7.99. Found: C,54.97; H, 6.47; N, 8.09.

EXAMPLE 9

(1) 4-Formyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

A solution of4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (2.31 g) indry tetrahydrofuran (25 ml) is mixed with 50% sodium hydride (480 mg)and stirred at room temperature for 1.5 hours. Under ice cooling, asolution of methyl iodide (1.7 g) in dry tetrahydrofuran (5 ml) is addeddropwise thereto over 5 minutes. The mixture is stirred further for 1.5hours at room temperature and poured into ice water, which is extractedwith ether. The extract is washed with water, dried and evaporated todryness. The residue is applied to liquid chromatography eluted withbenzene/hexane (5:1) to give the title compound (1.62 g): Yield 66.2%.

Mp. 119°-123° C.

(2) The same procedure as described above gives4-formyl-4-methyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.

Mp. 88.5°-90° C.

IR: ν_(max) ^(CHCl) 3 1720 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 1.28t(J=7, 3H) 1.53s(3H) 3.99q(J=7, 2H) 9.57s(1H).

EXAMPLE 10

(1)4-Methylaminomethyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

In the same procedure as described in Example 2,4-formyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole isallowed to react with methylamine to give the title compound: Yield97.4%.

NMR: δ_(CDCl).sbsb.3 0.72brs(1H) 1.38s(3H) 2.37s(3H) 3.80(3H).

Hydrochloride: mp. 222°-225° C.

Anal. Calcd. for: C₁₅ H₂₁ N₂ SCl: C, 60.69; H, 7.13; N, 9.44. Found: C,60.54; H, 7.46; N, 9.39.

(2) The same procedure as described above gives compound Nos. 10-2-10-6in Table 5.

EXAMPLE 11

4-N-Dimethylaminomethyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole

In the same procedure as in Example 3,4-formyl-4,5-dimethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole isallowed to react with dimethylamine to give the title compound as anoil: Yield 31.3%.

NMR: δ_(CDCl).sbsb.3 1.40s(3H), 2.10s(6H) 3.83s(3H).

Oxalate: mp. 168°-171° C. (decomp.).

Anal. Calcd. for C₁₈ H₂₆ N₂ O₅ S: C, 56.53; H, 6.85; N, 7.32 S, 8.38.Found: C, 56.61; H, 6.55; N, 7.04; S, 8.51.

EXAMPLE 12

4-Methylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole1-oxide

A solution of4-methylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole(1.3 g) in methanol (30 ml) is mixed with an aqueous solution (10 ml) ofsodium periodide (1.12 g) and kept at room temperature for 5 hours. Theprecipitate is filtered off and the filtrate is condensed. The residueis dissolved in methylene chloride, washed with water, dried andevaporated to give the title compound (1.28 g) as an oil: Yield 92.8%.

IR: ν_(max) ^(CHCl) 3 1010 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 1.35t(J=7, 3H) 2.41s(3H) 4.17q(J=7, 2H).

Oxalate: mp. 213°-217° C. (decomp.).

Anal. Calcd. for C₁₇ H₂₂ N₂ O₅ S: C, 55.72; H, 6.05; N, 7.64 S, 8.75.Found: C, 55.54; H, 6.07; N, 7.54 S, 8.61.

EXAMPLE 13

(1)4-Methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole1-oxide

(a) A solution of4-methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole(3.2 g) in dry tetrahydrofuran (30 ml) is allowed to react withtriethylamine and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile in thesame manner as in Example 6(a) to give4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole:Yield 87.0%. Mp. 111.5°-114° C. (decomp.) (b) The above product istreated in the same procedure as in Example 12 to give4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole1-oxide. Mp. 218°-220.5° C. (decomp.). The product is dissolved inmethylene chloride (20 ml) and trifluoroacetic acid (4 ml) is addedthereto. The mixture is kept at room temperature for 2 hours and thentreated in the usual manner to give the title compound (1.13 g): Yield89.7%.

Mp. 208°-212° C.

IR: ν_(max) ^(CHCl) 3 1010 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 1.41brs(1H) 2.48s(3H) 3.72s(3H).

Anal. Calcd. for C₁₄ H₁₈ N₂ OS: C, 64.09; H, 6.91; N, 10.68. Found: C,64.05; H, 6.93; N, 10.46.

(2)4-Methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole1,1-dioxide

A solution of4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole(1.7 g) obtained in above (1) (a) in chloroform (20 ml) is mixed with asolution of m-chloroperbenzoic acid (2.37 g) in chloroform (30 ml) underice-cooling with stirring and the mixture is kept at room temperaturefor 3 hours. The reaction mixture is washed with a sodium hydroxideaqueous solution and water, dried and evaporated to give4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole1,1-dioxide.

Mp. 222°-224.5° C. (decomp.).

The above product is treated with trifluoroacetic acid in the samemanner as in the above (1) (b) to give the title compound (880 mg):Yield 64.7%.

Mp. 170°-175° C.

IR: ν_(max) ^(CHCl) 3 1280, 1130 cm⁻¹.

NMR: δ_(CDCl).sbsb.3 1.33brs(1H) 2.47s(3H) 3.73s(3H).

Anal. Calcd. for C₁₄ H₁₈ N₂ O₂ S: C, 60.41; H, 6.52; N, 10.06. C, 60.61;N, 6.52; N, 9.72.

    TABLE 5      ##STR14##           Experimental Analysis      Formula:    NMR: δ.sub.CDCl.sbsb.3       Calculated: Comp. Substituent Yield or mp.sup.1 Found: No. R.sup.1     R.sup.2 R.sup.3 (%) IR: ν.sub.CHCl.sbsb.3 cm.sup.-1 (°C.)      S     CHNCl  2-2 Me Et H 91.9 1.08(J=7, 3H) 3.65s Oxalate C.sub.15 H.sub.20     N.sub.2 S.C.sub.2 H.sub.2 O.sub.4      (3H) 230-233(d) 58.276.337.99        58.086.267.91 2-3 Me i-Pr H 93.1 1.07d(J=7, 6H) 3.65s Oxalate     C.sub.16 H.sub. 22 N.sub.2 S.C.sub.2 H.sub.2      O.sub.4      (3H) 220-224(d) 59.326.647.69        59.386.467.45  2-4 Me      ##STR15##      H 91.8 3.60s(3H) HCl salt239-243(d) C.sub.19 H.sub.26 N.sub.2           7      S.HCl65.03.557.9810.1064.867.777.9310.36  2-5 Et Me H 94.9 1.28t(J=7,     3H) 2.41s Oxalate C.sub.15 H.sub.20 N.sub.2 S.C.sub.2 H.sub.2 O.sub.4       (3H) 4.12q(J=7, 2H) 208-210.5(d) 58.276.337.99        57.966.337.83     2-6 Et Et H 95.5 4.13q(J=7, 2H) Oxalate --       210-213.5(d) 2-7 Et     i-Pr H 95.0 1.08d(J=6, 6H) Oxalate C.sub.17 H.sub.24 N.sub.2 S.C.sub.2     H.sub.2 O.sub.4      1.33t(J=7, 3H) 189-193(d) 60.296.927.40      60.236.947.36 2-8 CH.sub.2 Ph Me H 95.3 1.50brs(1H) 2.25s(3H) HCl salt     C.sub.20 H.sub.22 N.sub.2 S.HCl      5.30s(2H) 209-213(d) 66.936.467.80           66.646.457.70      2-9 Et H     ##STR16##      94.2 1.23t(J=7, 3H)2.15s(6H) 4.08q(2H) Dioxalate207-210 C.sub.18     H.sub.27 N.sub.3 S.2C.sub.2 H.sub.2 O.sub.453.116.288.4552.846.458.17     3-2 Me Et Et 84.5 0.967t(J=7, 6H) 3.53s 93-95 C.sub.17 H.sub.24 N.sub.2     S      (3H)  70.798.399.71        70.658.369.57             3-3 Me     ##STR17##      64.5 2.27s(3H) 3.63s(3H) -- C.sub.18 H.sub.25 N.sub.3 S.2HCl.H.sub.2     O53.207.1910.3453.22 7.3110.05  3-4 Et Me Me 82.1 1.35t(J=7, 3H) 2.30s     67-69 C.sub.16 H.sub.22 N.sub.2      S      (6H) 4.15q(J=7, 2H)  70.038.0810.21        69.898.0510.00      3-5 Et      ##STR18##      94.5 12.5t(J=7, 3H) 121.5-124 C.sub.19 H.sub.26 N.sub.2      S72.568.338.9172.328.258.61  3-6 CH.sub.2 Ph Me Me 63 2.17s(6H)     5.36s(2H) -- -- 4-2 H Me Me 93.5 2.32s(6H) 10.26brs(1H) 138.5-139.5     C.sub.14 H.sub.18 N.sub.2 S        68.257.3611.37        68.317.3611.11     5-2 COCH.sub.3 Me Me 92 2.27s(6H) 2.68s(3H) Oxalate C.sub.16 H.sub.18     N.sub.2 OS.C.sub.2 O.sub.4 H.sub.2      3.97m(1H) 176-179 57.135.867.40         IR: ν.sub.CHCl.sbsb.3 1690 cm.sup.-1  56.815.867.11 5-3 COC.sub.2     H.sub.5 Me Me 91.9 1.36t(J=7, 3H) 2.30s HCl salt C.sub.17 H.sub.22     N.sub.2 OS.HCl      (6H) 4.03m(1H) 242-246(d) 60.246.848.27      IR:     ν.sub.CHCl.sub.3 1690 cm.sup.-1  60.076.898.04 6-2 CH.sub.2      CHCH.sub.2 Me H 91.3 1.35brs(1H) 2.43s(3H) Oxalate C.sub.16 H.sub.20     N.sub.2 S.C.sub.2 O.sub.4      H.sub.2      1640, 980, 185-188.5(d) 59.656.127.73      IR: ν.sub.CHC     l.sbsb.3 915 cm.sup.-1  60.016.237.56 6-3 CH.sub.2      CCH Me H 100 2.43s(3H) 2.22t(J=2, HCl salt C.sub.16 H.sub.18 N.sub.2     S.HCl      1H) 4.83d(J=2, 2H) 218-221(d) 62.636.249.13      IR: ν     .sub.CHCl.sbsb.3 3300, 2110 cm.sup.-1  62.686.228.82 6-4 COCH.sub.3 Me H     67.9 2.15s(3H) 3.30s(3H) 186-189 C.sub.15 H.sub.18 N.sub.2 OS      IR:     ν.sub.CHCl.sbsb.3 1630 cm.sup.-1  65.666.6110.2111.69        66.096.671     0.0411.40      6-5     ##STR19##      Me H 100 1.60brs(1H) 2.39s(3H)4.95s(2H)IR: ν.sub.CHCl.sbsb.3 1650     cm.sup.-1 131-133.5 C.sub.19 H.sub.27 N.sub.3      OS66.057.8812.1665.797.7612.37      6-6     ##STR20##      Me H 93.6 1.40brs(1H) 2.28s(6H)2.44s(3H) 4.18m(2H) 2HCl salt268-270(d)     C.sub.17 H.sub.25 N.sub.3 S.2HCl54.257.2311.1618.8353.997.1510.8918.55     10-2.sup.3 Me Et H 97.0 0.60brs(1H) 1.00t(J=7, HCl salt C.sub.16     H.sub.22 N.sub.2 S.HCl      3H) 1.36(3H) 3.77s(3H) 236-240 61.827.469.01            61.607.468.89 10-3.sup.3 Me i-Pr.sup.4 H 96.1 0.60brs(1H) HCl     salt C.sub.17 H.sub.24 N.sub.2 S.HCl      0.95d 0.98d(J=6, 6H) 227-229.5 6     2.847.768.62      1.37s(3H) 3.77s(3H)  62.707.778.54  10-4.sup.3 Me      ##STR21##      H 96.9 1.26brs(1H) 1.38s(3H)2.13(6H) 3.77s(3H) Dioxalate219-222     C.sub.18 H.sub.27 N.sub.3 S.2C.sub.2 H.sub.2      O.sub.453.116.288.4552.946.528.18  10-5.sup.3 Et Me H 95.0 0.75brs(1H)     HCl salt C.sub.16 H.sub.22 N.sub.2 S.HCl      1.33t 1.39s(3H) 194-198     61.827.469.01      2.35s(3H) 4.30q(J=7,  62.067.478.81      5H) 10-6.sup.     3 Et Et H 90.9 0.83brs(1H) HCl salt C.sub.16 H.sub.24 N.sub.2 S.HCl     0.98t(J= 7, 3H) 1.30t 203-206 62.847.768.62      (J=7, 3H) 1.37s(3H)     62.717.738.68     Notes:     .sup.1 d = decomposition,     .sup.2 Cyclohexyl,     .sup.3 The compound is substituted by methyl at the 4 position.     .sup.4 Isopropyl.

What we claim is:
 1. A compound of the formula: ##STR22## wherein R¹ is C₁₋₃ alkyl and R² is C₁₋₃ alkyl, or a pharmaceutically acceptable salt of said compound.
 2. A compound claimed in claim 1 wherein R¹ is methyl.
 3. A compound claimed in claim 1 wherein R² is methyl.
 4. The compound claimed in claim 1 which is 4-methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 5. The compound claimed in claim 1 which is 4-methylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 6. The compound claimed in claim 1 which is 4-ethylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 7. The compound claimed in claim 1 which is 4-isopropylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 8. The compound claimed in claim 1 which is 4-ethylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 9. The compound claimed in claim 1 which is 4-isopropylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 10. The compound claimed in claim 1 which is 4-methylaminomethyl-5-propyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole.
 11. The compound claimed in claim 1 which is 4-methylaminomethyl-5-isopropyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole. 